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Structure of cyclin-dependent kinase 2 (CDK2) in complex with the specific and potent inhibitor CVT-313

2020; Wiley; Volume: 76; Issue: 8 Linguagem: Inglês

10.1107/s2053230x20009243

2053-230X

Sumalatha Rani Talapati, Vijayashankar Nataraj, Manoj Pothuganti, Suraj T. Gore, Murali Ramachandra, Thomas Antony, Sunil More, Narasimha Rao Krishnamurthy,

Ubiquitin and proteasome pathways

CVT-313 is a potent CDK2 inhibitor that was identified by screening a purine-analogue library and is currently in preclinical studies. Since this molecule has the potential to be developed as a CDK2 inhibitor for cancer therapy, the potency of CVT-313 to bind and stabilize CDK2 was evaluated, together with its ability to inhibit aberrant cell proliferation. CVT-313 increased the melting temperature of CDK2 by 7°C in thermal stabilization studies, thus indicating its protein-stabilizing effect. CVT-313 inhibited the growth of human lung carcinoma cell line A549 in a dose-dependent manner, with an IC 50 of 1.2 µ M , which is in line with the reported biochemical potency of 0.5 µ M . To support the further chemical modification of CVT-313 and to improve its biochemical and cellular potency, a crystal structure was elucidated in order to understand the molecular interaction of CVT-313 and CDK2. The crystal structure of CDK2 bound to CVT-313 was determined to a resolution of 1.74 Å and clearly demonstrated that CVT-313 binds in the ATP-binding pocket, interacting with Leu83, Asp86 and Asp145 directly, and the binding was further stabilized by a water-mediated interaction with Asn132. Based on the crystal structure, further modifications of CVT-313 are proposed to provide additional interactions with CDK2 in the active site, which may significantly increase the biochemical and cellular potency of CVT-313.